Down syndrome is the most common genetically defined cause of mental retardation in human beings. There are about 250 thousand people with DS in the US and this number is likely to continue rising due to the current trend towards an increased life expectancy. In general, the cells of individuals with DS have one extra chromosome 21. This genetic condition affects the nervous system in many different ways besides producing different degrees of mental retardation. Individuals with DS have an increased incidence of seizure disorders and exhibit abnormalities of neuromuscular tone, audiovestibular function, ocular movements and visual acuity. They also develop a neuropathology indistinguishable from Alzheimer's disease after the third decade of life. Currently, Ts65Dn mice are the prime animal model for the mental deficit in DS. These mice are trisomic for a chromosomal segment homologous to a large portion of human chromosome 21. In behavioral tests, Ts65Dn mice display significant learning deficits. More recently, another partially trisomic mouse model for DS, called Ts1Cje, has been described. It has a trisomic segment only slightly shorter than the Ts65Dn segment and a comparatively milder learning deficit. The overall hypothesis is that the region of difference between the trisomic segments of these two mouse strains may contain genes responsible for a significant portion of the learning deficit seen in Ts65Dn mice, and possibly in persons with DS. The identification of such genes may provide targets for a rational pharmacotherapy for DS. This proposal has three specific aims: 1) Test the hypothesis that some forms of synaptic plasticity are selectively altered in aneuploid mouse models for DS; 2) Test the hypothesis that dendritic morphology is altered in mouse models for DS; 3) Test the hypothesis that three copies of specific single genes are necessary for the expression of part of the learning deficit seen in Ts65Dn mice by analyzing the phenotype of crosses between Ts65Dn and knockout mice.